1,2,3,4-Tetrahydro-γ-carbolinium salts: Novel reactions with thiols, mediated by polymer-supported reagents

Article abstract of DOI:10.1016/j.tetlet.2004.04.078

A series of dialkyl-[2-(3-alkylsulfanylmethyl-1H-indol-2-yl)-ethyl]amines was produced using a novel route involving nucleophilic ring opening of 2,2-dialkyl-1,2,3,4-tetrahydro-γ-carbolinium salts with thiols. The insertion reaction was mediated by a strong, polymer-supported base, and the purification of the target compounds was facilitated using resin-bound sulfonic acid.

Full text of DOI:10.1016/j.tetlet.2004.04.078

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4781–4783
1,2,3,4-Tetrahydro-c-carbolinium salts: novel reactions with thiols,
mediated by polymer-supported reagents
Mike E. Lizarzaburu and Stephen J. Shuttleworth*
Tularik Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA
Received 18 February 2004; revised 22 March 2004; accepted 8 April 2004
Abstract—A series of dialkyl-[2-(3-alkylsulfanylmethyl-1H-indol-2-yl)-ethyl]amines was produced using a novel route involving
nucleophilic ring opening of 2,2-dialkyl-1,2,3,4-tetrahydro-c-carbolinium salts with thiols. The insertion reaction was mediated by a
strong, polymer-supported base, and the purification of the target compounds was facilitated using resin-bound sulfonic acid.
Ó 2004 Published by Elsevier Ltd.
The reaction of 2,2-dialkyl-1,2,3,4-tetrahydro-c-carbo-
linium salts with carbon-based nucleophiles has been
disclosed in the literature.1–3 However, there are no
reported examples of reactions of these substrates with
simple aliphatic and aromatic thiols. We have discov-
ered that this nucleophilic ring opening reaction is a
robust and versatile synthetic protocol, and can be
conveniently mediated by polymer-supported reagents.
Scheme 1 illustrates the procedure developed. The Fischer
cyclization of phenylhydrazine 1 (1.0equiv) with N-alkyl-
piperidone 2 (1.05 equiv) in a solution containing 7%
O
R2
1. H2SO4 (7%) in Dioxane, 80o C, 1 h
N
R1
R1
+
N
H
NHNH2
N
R2
1
2
3
R2
N+
2. R3 X (4), DMF, rt, 3 h
R1
R3
or 4, NaHCO3, DMF, 50o C, 8 h
N
H
_
X
5
R4
S
, Dioxane/DMF (5:1), 50o C, 48 h
3. R4 SH (6),
TBD
R1
R2
N
N
4.
5. NH3 (2M) in MeOH
SO3H
H
R3
7
Scheme 1.
* Corresponding author. Tel.: +1-650-825-7411; fax: +1-650-825-7433; e-mail: sshuttleworth@tularik.com
0040-4039/$ - see front matter Ó 2004 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2004.04.078

4782
M. E. Lizarzaburu, S. J. Shuttleworth / Tetrahedron Letters 45 (2004) 4781–4783
Table 1
Table 2
R2
R
Me
R3
Me
R1
N
N
N
H
N
H
Me
Me
Entry
1
R
%Conversion7
Entry
1
R1
R2
R3
%Con-
version7
84
S
S
5-Me
Me
Me
90
Cl
2
3
95
86
OMe
S
S
S
S
2
5-Me
85
Cl
4
92
3
4
5-Me
5-Me
Me
Me
93
83
S
S
5
6
87
80
N
S
S
S
S
N
S
O
N
N
7
8
86
86
5
6
5-Me
5-Me
Me
Me
94
61
S
S
N
O
S
S
N
H
F
9
88
91
87
S
Cl
Me
7
5-Me
Me
42
Cl
10
11
S
S
S
S
8
9
5-Me
5-Me
Me
Me
94
68
CF3
F
S
12
13
89
94
N
S
Me
Cl
105,7-Di-F
Me
Me
66
72
S
S
H
N
S
Cl
14
15
91
94
11
5-SO2NH2
O
S
OCF3
Cl
12
13
H
Me
Me
76
77
S
S
Cl
4,6-Di-Cl
S
concentrated sulfuric acid in 1,4-dioxane proceeded
smoothly to furnish the tetrahydrocarboline 3, typically in
greater than 90% conversion.4 Quaternization of the basic
nitrogen was accomplished by treating 3 with a 1:4 v/v
mixture of an alkyl halide, 4, and N,N-dimethylforma-
mide (DMF). An alternative method, used in cases where
this procedure proved to be a little sluggish, involved
treating 3 with a solution of haloalkane and DMF (1:5 v/v
ratio) in the presence of 5 equiv of sodium bicarbonate,
and warming to 50 °C; the desired intermediate was then
isolated following filtration. A solution of the tetrahy-
drocarbolinium salt (5) in DMF was then added to a
stirred suspension containing 2 equiv each of a thiol, 6,
and polymer-supported 1,5,7-triazabicyclo[4.4.0]dec-5-
ene (TBD)5 in 1,4-dioxane, and the resulting reaction
Cl
14
15
16
5-CF3
Me
Me
Me
72
26
51
S
Cl
5,7-Di-Me
7-Br
S
Cl
S
Cl
17
18
5-Me
5-Me
4-OCF3-Bn
70
80
S
Cl
C(O)-t-Bu
S

M. E. Lizarzaburu, S. J. Shuttleworth / Tetrahedron Letters 45 (2004) 4781–4783
4783
mixture was agitated at 50°C for 2 days. The suspension
was then filtered, and the filtrate poured onto sulfonic acid
resin (5equiv).6 After 30min, the resin was washed thor-
oughly with methanol, and the desired product, 7, was
isolated following treatment of the resin with a 2 M
solution of ammonia in methanol, followed by evapora-
tion of the resulting filtrate under reduced pressure. Table
1 highlights the results obtained using a range of sulfur-
based nucleophiles using this protocol.8
mediated by supported reagents, making it a useful
synthetic procedure for parallel synthesis.
References and notes
ꢀ
1. Diker, K.; Maindreville, M. D.; Levy, J. Tetrahedron Lett.
1995, 36, 3511–3512.
ꢀ ꢀ
2. Sapi, J.; Grebille, Y.; Laronze, J.; Levy, J. Synthesis 1992,
383–386.
3. Zinnes, H.; Schwartz, M. L. U.S. (1976), US 3931229
19760106 Application: US 74-458916 19740408; CAN
84:90000; AN 1976:90000.
As part of a broader exercise, we subsequently examined
a series of reactions incorporating additional sulfur-
based nucleophiles with a varied set of substrates (Table
2). Generally, these insertion reactions proceeded
smoothly as had been observed previously, though we
did notice that, unlike with the majority of analogues
synthesized in this study, some of the products resulting
from thiophenol insertions tended to gradually decom-
pose following isolation. Further, reactions involving
electron-poor thiols gave less clean product mixtures.
We were also interested to discover that insertion reac-
tions involving 2-benzyl mercaptan with indole ring-
substituted substrates also proceeded with good
conversion.
4. For the original report outlining the construction of
tetrahydro-c-carbolines, see: (a) Cook, A. D.; Reed, K. J.
J. Chem. Soc. 1945, 402; For a more recent example of an
alternative method for the construction of these heterocy-
cles, see: (b) Zhang, L.; Meier, W.; Wats, E.; Costello, T.
D.; Ma, P.; Ensinger, C. L.; Rodgers, J. M.; Jacobsen, I.
C.; Rajagopalan, P. Tetrahedron Lett. 1995, 36, 8387–
8390.
5. Commercially available from Polymer Laboratories Ltd,
catalogue #3414-1679.
6. Commercially available from Polymer Laboratories Ltd,
catalogue #3404-4679.
7. Percentage conversion to the desired products was deter-
mined by HPLC at 220and 254 nm using an Agilent 1100
LC/MSD VL ESI system.
In summary, this short communication illustrates the
first reported example of nucleophilic ring opening
reactions of 2,2-dialkyl-1,2,3,4-tetrahydro-c-carbolin-
ium salts with thiols. The reaction is a valuable route
into a diverse array of sulfide derivatives, and can be
8. Analytical data for Table 1, entry 2: dH (400 MHz, CDCl3)
9.45 (1H, s), 7.45–7.35 (1H, m), 7.30–7.20 (5H, m), 7.10
(1H, m), 3.92 (2H, s), 3.88 (2H, s), 3.30–3.22 (2H, m), 3.18–
3.12 (2H, m), 2.75 (6H, s), 2.45 (3H, s). Mþ1 found 373.4;
C21H26ClN2S requires 372.14.